3-enol ethers of 2-formyl-3-oxo-5alpha-steroids and process for preparing same



of 2-formyl-3-oxo-5a-steroids.

Patented Dec. 8, 1964 ROmS AND PROCESS FQR PREPARING SAME Derek Burn, Bernard Ellis, and Vladimir Petr-ow, London,

England, assignors to The British Drug Houses Limited HOE C No Drawing. Filed Jan. 24, 1963, Ser. No. 253,750 2 Claims prierity, applicationQG/reat Britain, Han. 26, 1962, R

l 62 21 Claims. (Cl. 260-3914) A (v) where R is as hereinafter defined and R is H or Me, which compounds may be acylated, halogenated, oxidised and hydrogenated.

The present invention provides new 3-enol ethersof 2- formyl-3-oXo-5a-steroids including the Formula H below.

According to the present invention there is provided a process for the prepmation of 3-eno1 ethers of 2-formyl- 3-oXo-5a-steroids including the formula M 3,169,643 s-nnrn. nrnnns on 2-FORMYL-3-OXO=5oz-STE- This invention is for improvements in or relating to organic compounds and has particular reference to a new group of steroidal materials comprising the 3-eno1 ethers It is an object of the present invention to provide a novel and efficient procedure for introducing a carbon atom onto the Z-methyle-ne group adjacent to the B-keto group of the steroid molecule yielding a new series of compounds which possess valuable biological properties M9 or are intermediates for the preparation of compounds with valuable biological properties. Some of the 2-formyl derivatives (of Formula II below) which may be pre- 1 pared by the process or" the present invention possess g marked claudogenic proper-ties (V. P-etrow, J. Pharm. H Pharmacol, 1960, 12, 704) which render them of value l/ in, for example, the veterinary ,field. Thus the Sac-dihy- E drocortisone derivatives inhibit implantation in the E (II) mouse. Compounds derived from androstanolone and where R is O-alkyl, O-hydroxyalkyl, O-cycloalkyl or O- 17a-alkylandrostanolones and particularly the 19-nor dearalkyl and R is H or Me which process comprises treatrivatives thereof have claudogenic properties. They also ing a corresponding 3-enol ether derived from a 3-oxohave ovulation inhibition activity. The 2-formyl group Six-steroid saturated in Ring A including the formula in the formyl derivatives (of Formula 11 may addition- Me allybe converted into a methyl group or may be condensed with aromatic amines or other. carbonyl reagents yielding derivatives of value in the field of steroid technology. In addition, the 2-formyl derivatives (of For- R1 mula II may be condensed with such reagents as hydrazine or semicarbazide to yield pyraZolo-derivatives in- I cluding Formula III R Me H (I) where R and R have the same meaning. as above .with the Vilsmeier reagent folowed byhydrolysis. HO R The invention further provides a process for the prep- 6 aration of 3-enol ethers of 2formyl-3-oxo-5a-steroids in- NE E cluding the Formula 11 above which process comprises treating a 3,3-dialkoXy-5a-steroid saturated in Ring A i 7 including the formula I H Me where R is H or Me and with hydroxylamine to yield oxazolo derivatives including Formula IV Me Me 3 W t OH R i 1 W a Am a a (v1) l with not less than 2 molar equivalents of the Vilsmeier O 4 V p reagent followed by hydrolysis. V

H (IV) '60 The Vilsmeier reagent [see, for example, Houbenwhere R is H or Me. Compounds of types (111) and W yL o n d r Organische e. 4th (IV) are well established in the art on account of their Vol. 7(i), page 29 6t q.]' iS.kI1OW11 t Sk1116d 1I1 valuable anabolic properties (Clinton, Manson, Stonner, the artas an extremely convenient reagent-for'mtroducmg Beyler, Potts and Arnold, J. Amer. Chem. Soc., 1959, 81, the "formyl group into aromatic, quasi-aromatic and cer 1513; Clinton, Manson, Stonner, Christianson, Beyler, tain heterocyclic ring systems. Its present application Potts andArnold, J. Org. ChemJl96l, 26, 279). p to the S-enolic ethers derived from 3-oXo-5a-steroids The 2-formyl derivatives (of Formula K) may additionsaturated in Ring Arepresents a new, important, highly ally be reduced to give Z-hydroxymethyl derivatives inunexpected and specific development of the art.

eluding Formulav Starting materials.The 3-enol ethers derived from 3- oXo-a-steroids saturated in Ring A including Formula 1 form the starting materials of the present invention. They may be prepared by methods of prior art or as described below may be prepared and utilised in situ. Thus the 3-enol ethers may be prepared, inter alia, by such methods (of prior art) as (a) Conversion of the 3-oX0-5a-steroid saturated in Ring A into the 3,3-diallroXy derivative including partial Formula VI followed by elimination of AlkOI-I by pyrolysis or other methods of vprior art to yield the 3-enol ethers including Formula I,

(b) Treatment of the 3,3-dialkoxy derivative including partial Formula VI with the Vilsmeier reagent when the corresponding 3-enol ether including Formula I is obtained. Such enol ethers need not be isolated but may be formylated in situ with a further quantity of the Vilsmeier reagent to yield the formyl derivatives including Formula II,

(c) Treatment of an 3,3-alkylenedioxy derivative including partial Formula VII CHr-O tives and analogues thereof, the required 3-enol ethers may be prepared from the corresponding 3-oXo-A -steroids by conversion into the 3,5-dienic-3-enol ethers including partial Formula VIII (where R is as hereinabove defined) (VIII) followed by catalytic hydrogenation of the 3,5-dienic 3- enol ethers including partial Formula VIII when the 3- I enol ethers of the Ring A saturated Soc-steroids including Formula I are obtained.

Vilsmeier reagenL -The Vilsmeier reagent is generally understood to be a reactant formed from a formylated secondary amine and an acid halide selected from the group comprising those acid halides which readily undergo nucleophilic displacement of a halide ion on treatment with the N-forrnyl derivative of a secondary amine [see, for example, Bosshard and Zollinger, Helv. Chim. Acta, 1959, 42, 1659]. .7

Various formamides such as dimethylform amide diethylformamide methylphenylformarnide ethylphenylformamide formylpiperidine forrnylmorpholine methylethylformamide may be'employed. Dimcthylformamide is the preferred forrnarnide. 7

In addition to phosphorus oxychloride and phosgene, other acidic reagents such as phosphorus oxybrornide and pentachloride maybe employed Thionyl chloride, oXalylchloride and similar acid halides may also be used. ihosgene is the preferred reagent. i

Preferred procedure for preparing the Z-fOrmyI derivative.As stated hereinabove, ketalic derivative such as (VI) and (VII) are preferred as starting materials as they are generally more readily accessible than the correspond- N-enol ethers such as (I) and additionally are so readily converted in situ into the desired A -enol ethers such as (I) by reaction with the Vilsmeier reagent. In employing them. asstarting materials it will of course be necessary to use 2: 2 molar equivalents of the Vilsmeier reagent. When A -enol ethers such as (I) are employed as starting materials, however, it will in general be necessary to use 1: 1 molar equivalent of the Vilsmeier reagent.

The following experimental conditions are preferred for converting A -enol ethers such as (1) into the 2-formyl derivatives. When ketalic derivatives such as (VI) and (VII) are employed, the quantity of pho sgene used will be increased accordingly to l1'2 molar equivalents.

Phosgene (generally about one mole) either directly or in solution in an anhydrous non-hydroxylic organic solvent, which may be dioxan or preferably a halogenated hydrocarbon solvent uch as methylene dichloride, chloroform, carbon tetrachloride or ethylene dichloride is added at 0 C. to a solution of dimethylformamide, preferably in one of the foregoing chlorinated hydrocarbons or in dioxan, when formation of the Vilsmeier reagent occurs. It is preferable at this stage to obtain a reagent free from excess phosgene by ensuring the presence of not less than an equivalent quantity of dimethylformarnide and to prepare it under essentially anhydrous conditions.

The steroidal ether, either in solution (preferably in one of the foregoing halogenated solvents or in dioxan) or in the finely-powdered state, is then added at 0 C. to the prepared Vilsmeier reagent. The mixture is preferably stirred, moisture is excluded, and the reaction allowed to proceed spontaneously, when darkening of the solution occurs and the temperature of the mixture rises. In general, in working with small batches of material, external cooling is not necessary, but such cooling may become desirable when the scale of the reaction is increased. Reaction is generally complete in 1 to 3 hours. The mixture is then poured into aqueous methanolic sodium acetate solution to decompose the complex and the product isolated from the organic solvent layer.

Scope of the Z-jmmylation reaction.'l'he 2-formylation reaction is applicable to enolic derivatives including Formula I which may additionally contain further substituents as indicated below:

Hydroxyl gr0ups.-The Vilsmeier reagent is known by 7 prior art to formylate or replaceby halogen free hydroxyl groups (see Houben Weyl, loc. cit). It may be advantageous, therefore, to prote t hydroxyl groups by acylation and subsequently regenerate them by hydrolysis or hydrogenolysis if so desired. This is -particulariy desirable in the case of l7a-substituted-l7B-hydroxy derivatives.

Hydroxyl groups at C-. C and C interfere with the Vilsmeier reaction. Hydoxyl groups and functional derivatives thereofi'in such positions as 5, 6, ll, l2, l5, 16 (including l6-hydroxy methyl), l7, 18, 20 and 2i (including the condensation products of 15cc, 7m-glycols with carbonyl components), however, generally permit forrnylation at C to take place. Thiol groups at C are unaffected.

Carbonyl gr0ups.-Carbonyl groups such, for example, as carbonyl groups at l1, l2, l6, 17, 18 and 20, normally do not interfere with the forrnylation procedure.

' Carbalkoxy gr0r1ps.CarbaL oXy groups at C C and C vor in the sidechain do not interfere With the formylzu.

5 Alkenyl grupS.Vinyl and allyl groups at C do not interfere with the process of the invention.

Methylene and ethylidene groups.Such groups at positions 6, 11, 16(17), 16 and 17 do not interfere with the process of the invention.

Lactone, ether and spirokezal residues. Spirolactone residues such as O.CO.CH CH attached to C etheric groups at C and bridging C and C spiroketal moieties such as are present in diosgenone, do not interfere with the process of the invention.

Halogen groups-Chlorine, bromine or fluorine substituents in Rings C and D or in the side-chain do not interfere with the process of the invention.

Unsaturated lirzkages.-Unsaturated linkages at C C C C and C do not interfere with the process of the invention.

Ketol groups.-Ketol groups at C C C1qC2o and Czg-Cg are preferably acylated prior to reaction with the Vilsmeier reagent.

Corticoz'd sidechain.-The corticoid sidechain may be protected by acylation at C by reaction with formaldehyde to give the bis-methylenedioxy derivative, by forming the C -C cyclic carbonate or acetonide or by other methods known to those skilled in the art, and subsequently regenerated as desired.

Epoxides.-l6fi-Methyl-l6u, 17m-epoxypregnan-20-one derivatives may be converted in one operation into the corresponding 2-formyl derivatives of 17a-hydroxy-16- methylenepregnan-ZO-one by using approximately extra mole proportions of the Vilsmeier reagent. Epoxypregnan-ZO-one residues are converted into 16,8- halo-17a-hydroxypregnan-20-one structures.

The following 3-0X0-5ot-St61'0id8 and -19-nor analogues thereof and their acyl and other derivatives (such as bismethylenedioxy derivatives in the case of corticoids, acetonides and in the case of cis-a-glycols and ethers in the case of alcohols) thereof may be submitted to the process of the invention.

a-androstane-3,l7-dione and its 6- and 16-rnethyl derivatives, 6 and ll-methylene derivatives and the ll-oxoll-hydroxyand 9(l1)-dehydro derivatives thereof.

17/3-hydroxy-5a-androstan-3-one and its 6-rnethyl derivatives and the ll-oxo-ll-hydroxyand 9( ll)-dehydro derivatives thereof.

17cc alkyl 17fi-hydroxy-5a-androstan-3-ones (wherein the alkyl group contains up to 4 carbon atoms) and its 6-methyl derivatives and the ll-oxoil-hydroxy and 9(l1)-dehydro derivatives thereof.

17a alkyl-17 3-hydroxy-5a androstan-3-ones (wherein the alkyl group contains up to 4 carbon atoms).

17a-alkylnyl-17B-hydroxy 5a-androstan-3-ones (wherein the alkynyl group contains up to 5 carbon atoms).

5u-pregnane-3, ZO-dione and its 6 and 16-methyl derivatives and the ll-oxo, l'l-hydroxy and 9(11)-dehydro derivatives thereof.

17a-acetoxy-5e-pregnane-3,ZO-dione and the 6- and 16- methyland 16-methylene derivatives and the' ll-o'xo, 11- hydroxy and 9(l1)-dehydro derivatives thereof.

l7a-acetoxy-2l-fluro-Su-pregnane-3,20-dione and the 6 and 16-methyl and 16-methylene derivatives and the 11- oxo, ll-hydroxy and 9(11)-dehydro derivatives thereof.

Sa-dihydrocortisone and hydrocortisone and the 6- methyl, 16-methyl, 16-methylene, 16u-hydroXy derivatives thereof.

1602,170: isopropylidenedioxy Sa-pregnanelZG-dione and the G-methyl derivative and the ll-oxo, li-hydroxy and 9(ll)-dehydro derivatives thereof.

5a-dihydro-compound S and the 6-methyl, 16-methyl,.

16-methylei1e, 16-hydroxy derivatives and the 9(1l.)-dehydro derivatives thereof.

3 (3 oxo-l7fi-hydroxy-5a-androst-l7a-yl)-propionie acid and lactone and the ll-oxo, ll-hydroxy and 9(11)- dehydro derivatives thereof.

. 5a-dihydrotestololactone.

3-oxo-5a-pregn-l7-enoic acid (esters) and the 6-methyl 6 derivative and the ll-oxo, ll-hydroxyand 9(1l)-dehydro derivatives thereof.

It will be seen that the 3-enol ethers of the 2-formyl- 3-oxo-5a-steroids derived from the compounds named above, comprise compounds of the general formula:

}B R: g

l l 0110 i H wherein R and R together may be 0x0 or O.CO.CH .CH

R is hydrogen, methyl, methylene or hydroxyl R and R together may be o on O \CH;

R is hydrogen or methyl, and V B is a single bond when R is oxo or hydroxy and is either a single or double bond when R is hydrogen.

Following is a description by way of example of methods of carrying the invention into effect.

' EXAMPLE 1 Preparation of 17a-Acetoxy-2-Formyl-3-Methoxy-5a- Pregn-Z-En-ZO-One l l H (a) A solution of 17a-acetoxy-3,3-dimethoxy-5apregnan-ZO-one [5.5 g. M.P. 190 to 191 C., needles, [0c] 4.0 (c, 0.97 in dioxan) prepared from the corresponding 3-ketone by treatment With methanol containing a trace of oxalic'acid] in dry ethylenedichloride ml.) containing a trace of pyridine was added at.0 C. with stirring to a suspension of the complex prepared from dimethylformamide (3.3 ml.) and phosgene (1.9 g.) in dry ethylenedichloride (30 ml.) and the mixture was allowed to Warm to room temperature over 3 hours. A solution of sodium acetate (7.5 g.) in methanol (50 ml.) and water (10 ml.) was added, stirring was continued for a further /2 hour, the mixture was poured into water, washed and dried (Na SO extract yielded a gummy residue which crystallised from dichloromethane/methanol to give 17a-acetoxy-2-forinyl-3-methoxy-5a-pregn-2- en-ZO-one as plates, M.P. 247 to 250 C., [a] +79.4 (c, 1.2 in chloroform),

OHC I MeO I 1'1 A solution of 17a-methyl-5a-andr0stan-l7fi-ol-3-one (1 g.) [Rusicka, 'Meister and Prelog, Helv. Chim. Acta, 1947,30, 867] and selenium dioxide (1 g.) in methanol (80 ml.) was heated under reflux for 1 hour, cooled, and a solution of potassium hydroxide (1 g.) in methanol (30 ml.) added. Water (500ml) was added, the product filtered off and recrystallised from aqueous methanol to give 3,3 dimethoxy 17a methyl-Sa-androstan-173-01, tablets M.P. 154 to 157 C.,

x21? 1180, 1145, 1100 and 1040 cm.

7 A solution of the foregoing compound (3 g.) in acetic anhydride (30 ml.) and pyridine (30 ml.) was boiled under reflux for 3 hours, cooled and poured into water (250 ml.). The product was extracted with benzene, the extract dried (Na- 50 filtered through a short column of alumina and the solvent evaporated. crystallisation of the residue from aqueous methanol (containing a trace of pyridine) gave 17,8-acetoxy-3,3-dimethoxy-Nix-methyl- Sa-androstane, plates, MP. 114 to 116 C., [a] +7 (c, 0.62 in chloroform). V v

The foregoing compound (1 g.) was added to a stirred ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene in ethylene dichloride w./v. 7 ml.) to asolution of dimethylformamide (1.2 ml.) in ethylene dichloride (10 ml.)] and the mixture stirred at room temperature for 1 hour. The mixture was hydrolysed with aqueous methanolic sodium acetate and the product isolated with ether. Crystallisation of the product from aqueous methanol gave 175 acetoxy 2-formyl-3-methoxy-17u-methyl-5aandrost-Z-ene, needles M.P. 182 to 183 C., [a] +95 (c, 0.82 in chloroform),

Nuiol .7... 1730. 1650and 1610 cat- A suspension of 21-acetoxy 3,3 dimethoxy 17a-hydI'OXY-SQ. pregnane 11,20 dione (Evans, Green, Hunt, Long, Mooney and Phillipp J.C.S., 1958, 1529) (10.5 g.) in dry ethylenedichloride (75 ml.) was added with stirring to a cooled suspension of' the complex prepared from phosgene (5 g.) and dimethylformamide (5 g.) in dry ethylenedichloride (75 ml.) and the mixture was allowed to Warm to room temperature over 4 hours. A solution of sodium acetate (10 g.) in methanol (75 ml.) was added and stirring was continued for a further /2 hour. The mixture was poured into water and the steroid was extracted into ether. Evaporation of the water-Washed and dried extract left a residue which was crystallised from dichloromethane/methanol to give 21-acetoxy-2-formyl- 17a-hydroxy-3-methoxy-5u-pregn-2-ene 11,20 dione as plates, M.P. 263 to 265 C., [a] -{15l (0., 1.0 in pyridine),

ELOH 17fl-acetoxy-3,3 ethyIenediQXy-Sa androstane (1.5 g. M.P. 140.5 to 141.5 C.) was added to an ice-cooled stirred suspension of the Vilsmeier reagent [prepared from solutions of dimethylformamide (1.5 ml.) in ethylene dichloride (10 ml.) and phosgene in ethylene dichloride (10%, V 10 ml.)]. The mixture was stirred for 1 hour, allowed to stand for 16 hours at room temperature, then hydrolysed with aqueous methanolic sodium acetate solution. The product was isolated with ether as a pale yellow solid. Recrystallisation from ethanol gave 17fl-acetoxy-3-(2-formoxyethoxy)-2 formylandrost 2 ene, as prisms, M.P. 200 to 201 C., [a] +81 (c., 0.89 in chloroform) rage 274 mp. (6 12,960) my 1720, 1645 and 1610 cmf EXAMPLE 6 Preparation of 1 7,8-Acetavy-Z-Formyl-S-Metlzoxy-]9- NOr-Sd-Androst-Z-Ene A solution of 17/8-hydroxy-19-nor-5u-androstan-3-one (5 g.) [BoweraRingold and Denot, J. Amer. Chem. Soc, 1958, 80, 6115] in acetic anhydride (50 ml.) and pyridine (50 ml.) was heated on a steam bath for 1 hour. The mixture was cooled poured into water (1 l.) and the precipitated solid filtered 011 and washed with water. Recrystallisation of the product from aqueous methanol gave 17,8-acetoxy-19-nor-5a-androstan-3-one, prisms, M.P. 98-l00 C.

A solution of the foregoing compound-(4.2 g.) and oxalicacid (500 mg.) in methanol (100 ml.) was heated under reflux for 2 hours, cooled and pyridine (5 ml.)

added. The mixture was poured into Water (500' ml.)

andthe product isolatedwith ether. Crystallisation of the'product from aqueous methanol containing a trace .of pyridine gave 17li-acetoxy-3,3-dimethow-19-nor-5a-an- .drostane, prisms, M.P. 111113 C., [a] '+14.8 (0.,

1.01m chloroform),

The foregoing compound (300 mg.) was added to a stirred, ice-cooled suspension of the Vilsmeier reagent [prepared by addition of a solution of phosgene in ethylene dichloride (10% w./v., 5.5 ml.) to a solution of dimethyl formamide (1 ml.) in ethylene dichloride (3 ml.)] and the mixture stirred at room temperature for 2 hours. The mixture was hydrolysed with aqueous methanolic sodium acetate solution and the product isolated with ether. crystallisation of the product trom aqueous methanol gave 17 3-acetoxy-2-formyl-3-methoxy-19 -nor- 5a-androst-2-ene, plates, M.P. 188-190 C., [oz] -l148 (c., 1.03 in chloroform),

3:31? 1730, 1650 and 1610 omf EXAMPLE 7 Preparation of 21 -Acetoxy-2-F0rmyl-1 7a-Hydroxy- 3-Methoxy-5a-Pregn-2-En-20-One A solution of 21-acetoxy-17a-hydroxy-5a-pregna3,20- dione [5 g. (Rosenkranz and Patalri, U.S.P. 2,596,562)] and oxalic acid (200 mg.) in methanol (100 ml.) was boiled under reflux for 3 hours. The mixture Was cooled, treated with pyridine, poured into water (1.1) and the product isolated with ether. crystallisation gave 21- acetoxy-17m-hydroxy-3,3-dimethoxy=5u-pregnan-20-one.

The foregoing compound (1 g.) was added to a stirred ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene in ethylene dichloride (10% W./V., 7 ml.) to a solution of dimethylformamide (1.2 ml.) in ethylene dichloride 10 ml.)] and the mixture stirred at room temperature for '1 hour. The mixture was hydrolysed with aqueous methanolic sodium. acetate and the product isolated with ether. crystallisation of the product gave 2.1-acetoxy-2-formyl-17a-hydroxy-3-methoxy-5a-pregn-2-en-20-one,

35,32? 279 mu (613,200), 213? 1740, 1730, 1650 and 1610 c111.

EXAMPLE 8 Preparation of 21-Acetoxy-Z-Formyl-I7a-Hydr0xy- 3-Methoxy-16fi-Methyl-5a-Pregn-2-En-1I,20-Dione H20 A. C

, -orr of M. Me

A solution of 21-acetoxy-17a-hydroxyel6 3-methyl-5apregna-3,11,20-trione g. (Nathansohn, Winters and Testa, Experientia 1961, 17, 448)] and oxalic acid (200 mg.) in methanol (100 ml.) was heated under reflux for 2 hours. The mixture was cooled, treated with pyridine (5 ml.) and poured into water (1 1.). The product was isolated with ether and crystallised to give 21- acetoxy 17cc hydroxy 3,3 dimethoxy-16,8-methy1-5apregna-l 1,20-dione.

The foregoing compound (3 g.) was added to a stirred, ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene in ethylene dichloride w./v., 21 ml.) to a solution of dimethylkm) 279 mu 613,500 13391740, 1730, 1705, 1650 max.

and 1610 cm."

EXAMPLE 9 Preparation of 2-Formyl-17a-Hydroxy-3-Methoxy- 1 6a-Methyl-5a-Pregn-2-En-1l ,ZO-Dione A solution of 17a-hydroxy-lGa-methyI-Sa-pregna- 3,11,20-trione [2.5 g. (Heusler, Kebole, Meystre, Ueberwasser, Wieland, Anner and Wettstein, Helv. Chim. Acta, 1959, 42, 2043)] and oxalic acid mg.) in methanol (40 ml.) Was heated under reflux for 4 hours, cooled and treated with pyridine (3 ml.). The mixture was poured into water (500 ml.), the product isolated with ether and crystallised to give 17a-hydroxy-3,3-dirnethoxy l6umethyl-Smregn-I 1,20-dione,

313i? 1730, 1705 cm.-

A solution of the foregoing dimethoxy compound (500 mg.) in ethylene dichloride (5 ml.) was added to a stirred ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene in ethylene dichloride 10% w./v., 3.5 ml.) to a solution of dimethylform-amide (0.6 ml.) in ethylene dichloride (5 ml.)] and the mixture stirred at room temperature for 1 hour. The mixture was hydrolysed with aqueous methanolic sodium acetate and the product isolated with ether. crystallisation of the product gave 2-formyl-17ahydroxy-3-methoxy 16cc methyl-Sa-pregn-Z-en-l1,20- dione,

X232? 278.5 my. (5 13,650), ,331? 1730, 1705, 1650, 1610 emf EXAMPLE 10 Preparation of 21 -A cetoxy-Z-Formyl-J 7 a-Hydroxy-3- M ethoxy-J 6 a-M ethyl-5 a-Pregna-2,9 (1 1 )-Dien-20-One (EH10 A G pregn-9(ll)-en-3,20-dione (3.7 g.) (Ehrmann, Heusler, Meystre, Wieland and Wettst'ein, Helv. Chim. Acta, 1959,

42, 2548) andoxalic acid (100 mg.) inmethanol (50 Preparation of 71 fi-A cetoxy-Z-Frmyl-3-Meth0xy-16B- M ethy 1-5 a-Androst-Z-Ene OHC Me O

A solution of 1713-acetoxy-16fi-methyl-5a-androstan-3- one (10 g.) (Rugguieri, Ferrari and Gandolgi, Gazz. Chim. Ital. 1961, 91, 686) and oxalic acid (250 mg.) in methanol (150 ml.) was heated under reflux for 3 hours. The mixture was cooled, pyridine (5 ml.) added and the mixture poured into water (1.2.1.). The product was isolated with ether and recrystallisedto give 17a-acetoxy- 3,3-dimethoxy-16B-methyl-5w-androstane,

in 1735 cm.-

A solution of the foregonig compound (5 g.) in ethylene dichloride (50 ml.) was added to a stirred, ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene in ethylene dichloride W./v., ml.) to a solution of dimethylformamide (6 ml.) in ethylene dichloride ml.)] and the mixture stirred at room temperature for 1 hour. The mixture was hydrolysed with aqueous methanolic sodium acetate and the product isolated with ether. crystallisation of the product gave 17,6-acetoxy-2-formyl-3-methoxy-16fi-methyl-5a-androst-2-en,

279 my (513,900) 333i? 1735, 1650, 1610 cm.-

EXAMPLE 12 Preparation of 1 7,8-A cetoxy-Z-F0rmyl-3-Mezlz0xy-1 7 o: M etlz yl 9-N 0r-5 lX-A ndrost-Z-Ene Me i EtOH max.

A solution of 175-hydroxy-17a-methy1-19-nor-5a-ar drostan-3-one (5 g.) (Bowers, Ringold and Dorfrnan, J. Amer. Chem. Soc., 1957, 79,4557) in acetic anhydride (50 ml.) and pyridine (50'ml.) was heated under reflux for 4 hours. The mixture was cooled, poured into water and the product isolated with ether. crystallisation gave- 17 fl-acetoxy-17wmethyl-19-nor-5 a-androstan-fi-one,

A solution of the foregoing compound (2.9 g.) and oxalic acid (100 mg.) in methanol (50 ml.) was boiled under reflux for 3 hours. The mixture was cooled, treated 1735, 1710 cm. i

with pyridine (5 'ml.) and poured into water (590 ml.).

The product was isolated with ether and crystallised to give 175 acetoxy 3,3-dimethoxy-17u-methyl-19-nor-5aandrostane E3? 1735 cm? a The foregoing compound (1 g.) was added to a stirred ice-cooled suspension of the Vilsmeier reagent [prepared by the addition of a solution of phosgene (10% w./v., 7 ml.) to a solution of dimethylformarnide (1.2 ml.) in ethylene dichloride (5 ml.)] and the mixture stirred at room temperature for 2 hours. The mixture was hydrolysed with aqueous methanolic sodium acetate and theproduct isolated with ether. Crystallisation of the product gave 17.f3-acetoxy 2 formyl 3 methoxy-17amethyl-19-nor-5a-androst-2-ene x313 279.5 m (612,900), my 1735, 1e50, 1610 cmr EXAMPLE 13 Preparation of 7fl-A cer0xy-2-F0rmyl-3-Meth0xy- 6 0a,] 7aDimethyl-5a-A ndrost-Z-Ene A solution of 6a,17a-dimethyI-Sa-andmstan-175-01-3- one (5.6 g.) (USP. 2,936,312) in pyridine (50 ml.) and acetic anhydride (50 ml.) was heated under reflux for 4 hours. The mixture was cooled, poured into water (1 l.) and the product isolated with ether. crystallisation of the product gave l7fi-acetoxy-6u,17a-dimethyl-5aandrostan-3-one,

:32 1735, 1715 (BIL-1 A solution of the foregoing compound (4 g.) and oxalic acid mg.) in methanol (60 nil.) was heated under reflux for 3 hours, cooled and the mixture treated with pyridine (4 ml). The mixture was poured into water (600 m1.) and the product isolated with other. Crystallisation of the product gave 17,8-acetoxy-3,3-dimethoxy- 6a,17a-dimethyI-Sa-androStane,

figif 1735 cmr The foregoing compound (1 g.) was added to a stirred ice-cooled suspension of the Vilsmeier reagent [prepared A552? 279 my (13,900 2:1 1735, 1e50, 1610 cm? EXAMPLE 14 1 7p-A cezoxy-2-Formyl-3-Metlzoxy- Preparation 0 f 5 a-A ndrost-Z-E I16 13 17,3 Acetoxy 3,3 dimethoxy 50c androstane [10 g., MR 143-444 0, prepared from the'corresponding 3-ketone by treatment with methanol containing a trace hg2? 2'79 111p. (513,800), 12,32 1740, 1560, 1620 cmf The 2-formyl derivatives prepared in the foregoing specific examples possess ciaudogenic activity.

We claim:

1. A S-enol ether having the formula wherein R is selected from the group consisting of O-lower alkyl and O-formoiry lower aliiyl;

R is selected from the group consisting of hydrogen and methyl R is selected from the group consisting of hydrogen,

oxo and hydroxy;

R is selected from the group consisting of hydroxy,

COCH COCH F, COCH OH and COCH O (acetyl) R is selected from the group consisting of hydrogen, lower alkyl, and lower alkynyl when R is hydroxy and is selected from the group consisting of hydrogen, hy-

. droxy and acetoxy when R is selected from the group consisting of COCH -COCH F, --COCH OH and COCH O acetyl) R and R when taken together are selected from the selectedfrom the group consisting of single and double bonds when R is hydrogen.

2. 17a-Acetory-2-formyl 3 methOXy-Su-pregn-Z-en- ZO-one.

3. l75-AcetoXy-2-formyl 3 methOXy-Ua-methyl-Saandrost-Z-ene.

4. 21-Acetoxy-2-tormyl-17 -hyclroxy 3 methOXY-Sogpregn-2-ene-11,20-dione.

5. 17f3-Acetoxy-2-formyl 3 methoxy-l9-nor-5aandrost-Z-ene. v

6. 21-AcetoXy-2-formyl-l7a-hydroxy 3 HlfitilOXY-Sotpregn-Z-en-ZO-one.

7. 21-Acetoxy 2 formyldh-hydroxy 3 methoxy- 16 ,B-methyl-S a-pre gn-2-en-1 1, ZO-dione.

8. Z-Formyl-lh-hydroxy 3 methoXy-l6a-methyl-5orpregn-2-en1l,20-dione.

9. 21-Acetoxy- 2 -formyl-l7u-hydroxy 3 methoxy- 16a-methyl-5a-pregna-2,9- 1l)-dien-20-one.

10. 17,6-Acetoxy-2-iormyl 3 meth0xy-l6B-methyl- 5u-androst-2-ene.

11. 17fi-Acetoxy-2-formyl 3 methoxy-lh-methyl- 19-nor-5a-androst-2-ene.

12. 17B-Acetoxy 2 formyl 3 methoxy-6u,17a-dimethyl-Sa-andrust-Z-ene.

13. l7p-AcetoXy-2d0rmyl-3-methoxy-5a-androst-2-enc.

14. A process :for the preparation of a 2(3) unsaturated 3'enol ether of a 2-formyl-3-oXo-5a-steroid selected from the group consisting of the androstane, 19-norandrostane, pregnane, l9-norpregnane, cholestane, spirostane, ergostane, and stigmastane series'comprising treating a corresponding 2(3) unsaturated 3-enol ether of a 3-0X0- Sci-steroid saturated in Ring A and unsubstituted at C with the Vilsmeier reagent followed by hydrolysis.

15. A process as claimed in claim 14 wherein the 3-enol ether steroid starting material is reacted with the Vilsmeier reagent under anhydrous conditions and the resulting complex is converted into the required formyl derivative by reaction with aqueous methanolic sodium acetate.

16. A process as claimed in claim 14 wherein the Vilsmeier reagent is a complex formed from dimethyl formamide and phosgene.

17. A process as claimed in claim 14 wherein the 3-enol ether steroid starting material in dry ethylene dichloride is treated at 0 C. withv a complex prepared from dimethylformamide and phosgene in dry ethylene dichloride.

18. A process as claimed in claim 14 wherein 1.0 molar proportion of the S-enol ether steroid starting material is employed together with at least 1 molar proportion of phosgene and dimethylformamide.

19. The process of claim 14 wherein the 2(3) unsaturated B-enol ether starting materim is a 3-alkoxy-A -5msteroid prepared in situ by treating a corresponding 3,3- dialkoxy-5a-steroid saturated in Ring A with the Vilsmeier reagent.

20. The process of claim 14 wherein the 2(3) unsaturated 3-enol ether starting material is a 3-hydroxya1koxy- A ia-steroid prepared in situ by treating a corresponding 3,3-alkylenedioXy-5u-ster0id saturated in Ring A with the Vilsmeier reagent.

21.,A process for the preparation of 2. 2(3) unsaturated 3-enol ether of a 2-formy-l-3-oxo-5a-steroid selected ing a corresponding 3,3-dialkoxy-5u-steroid saturated in Ring A and unsubstituted at C with at least 2 molar equivalents of the Vilsmeier reagent followed by hy-.

drolysis. I

No references cited.

LEWIS GOTTS, Primary Examiner. 

1. A 3-ENOL ETHER HAVING THE FORMULA 